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Adjunctive effect of hyperbaric oxygen treatment

after thrombolysis on left ventricular function in

patients with acute myocardial infarction
Milica Dekleva, MD, PhD,a Aleksandar Neskovic, MD, PhD, FESC,d Alja Vlahovic, MD,d
Biljana Putnikovic, MD, PhD,b Branko Beleslin, MD, FESC,c and Miodrag Ostojic, MD, PhD, FESC, FACCc
Belgrade, Serbia and Montenegro

Background The role of hyperbaric oxygen in patients with acute myocardial infarction is controversial, ranging
from not beneficial to having a favorable effect. This randomized study was conducted to further assess the benefit of hy-
perbaric oxygen treatment after thrombolysis on left ventricular function and remodeling in patients with acute myocardial
Methods Seventy-four consecutive patients with first acute myocardial infarction were randomly assigned to treat-
ment with hyperbaric oxygen treatment combined with streptokinase (HBO) or streptokinase alone (HBO).
Results There was a significant decrease of end-systolic volume index from the first day to the third week in HBO
patients compared with HBO patients (from 30.40 to 28.18 vs from 30.89 to 36.68 mL/m2, P .05) accompanied
with no changes of end-diastolic volume index in HBO compared with increased values in HBO (from 55.68 to 55.10
vs from 55.87 to 63.82 mL/m2, P .05). Ejection fraction significantly improved in the HBO group and decreased in
the HBO group of patients after 3 weeks of acute myocardial infarction (from 46.27% to 50.81% vs from 45.54% to
44.05 %, P .05).
Conclusions Adjunctive hyperbaric oxygen therapy after thrombolysis in acute myocardial infarction has a favor-
able effect on left ventricular systolic function and the remodeling process. (Am Heart J 2004;148:e14.)

Normobaric therapy has been in use for many years that study, HBO was administered in a chamber for 1
in the treatment of ischemic heart disease.1 When oxy- hour at 3 ATA (absolute pressure of 1 atmosphere), 1
gen is breathed in concentrations higher than those hour after hypoxia exposure. Results suggested that
found in the atmospheric air, it is considered to be a HBO, as a single therapy, is able to attenuate hypoxia-
drug. A limited amount of oxygen is dissolved in blood ischemia brain insult and offer neuroprotectivity. HBO
in normal atmospheric pressure, but under hyperbaric reduced neuronal injury with much less atrophy and
conditions, it is possible to dissolve sufficient oxygen, apoptosis of immature neurons, resulting in further
for example, 6%, in plasma to meet the usual require- improvement of sensorimotor function of neonatal
ments of the body. The oxygen physically dissolved in brain.
solution will be utilized more readily than that bound The role of HBO in patients with acute myocardial
to hemoglobin, and this effect may normalize or in-
infarction is controversial, ranging from no beneficial
crease oxygen tension in ischemic tissue.1
effect3,4 to a favorable effect.5,6 The only controlled
Calvert et al2 reported that hyperbaric oxygen (HBO)
trial done by Thurston et al,5 in the prethrombolytic
could be a treatment for neonatal hypoxia-ischemia in
era, revealed a trend but not a statistically significant
a neonatal rat model and could prevent brain injury. In
decrease in mortality rates, especially in high-risk pa-
tients. An animal study conducted by Thomas et al6
From aClinical Medical Center Dr Dradisa Misovic-Dedinje, bClinical Medical Center proved the hypothesis that a combination of thrombo-
Zemun, cInstitute for Cardiovascular Diseases Clinical Center of Serbia, and dInstitute lytic therapy and HBO would be more effective in re-
for Cardiovascular Diseases, Dedinje, Belgrade, Serbia and Montenegro.
ducing the size of the myocardial infarction than either
Reprint requests: Milica Dekleva, MD, PhD, Clinical Medical Center Dr Dragisa Miso-
vic-Dedinje. Department of Echocardiography. Milana Tepica 1 St, 11000 Belgrade, of these modalities alone. Therefore, a randomized pi-
Serbia and Montenegro. lot trial conducted by Shandling et al7 demonstrated
E-mail: mildek@eunet.yu
that adjunctive treatment with HBO appears to be fea-
0002-8703/$ - see front matter
2004, Elsevier Inc. All rights reserved. sible and safe for patients in the acute phase of myo-
doi:10.1016/j.ahj.2004.03.031 cardial infarction. Finally, the Hyperbaric Oxygen and
American Heart Journal
2 Dekleva et al
October 2004

Thrombolysis in Myocardial Infarction (HOT MI) study

Figure 1
demonstrated that treatment with HBO in combination
with thrombolysis might result in an attenuated creat-
ine phosphokinase rise, more rapid resolution of pain,
and improved ejection fraction (EF).8
The following randomized study was designed to
further assess the benefit of thrombolysis in combina-
tion with HBO on the remodeling process and left ven-
tricular function preservation in patients with acute
myocardial infarction.

Study population
The study population consisted of consecutive patients
with first myocardial infarction who met the following crite-
ria: (1) age 70 years, (2) chest pain lasting 30 to 360 min- Time distribution from thrombolysis to HBO.
utes, (3) ST-segment elevation 2 mm in 2 contagious elec-
trocardiographic leads, (4) transient creatine phosphokinase
and/or MB isoenzyme increase, and (5) first echocardiogram
performed within 24 hours of the onset of pain. HBO were pressurized during a 20-minute period up to 2
Exclusion criteria were standard for thrombolysis, includ- ATA. They remained at this pressure during 60 minutes in
ing suspected aortic dissection, recent surgery, recent peptic the monoplace hyperbaric chamber. Decompression time
ulcer, and stroke. Exclusion criteria also included patients was 20 minutes with decreasing pressure change 0.2 ATA/
with malignant arrhythmias and severe hemodynamic instabil- min. A critical care nurse and cardiologist were in attendance
ity, with Killip classes III and IV, nonrapidly controlled with at all times. By using electrocardiographic cables with 3 ter-
intravenous medication, and patients with previous myocar- minals, all patients in the chamber were monitored, includ-
dial infarction or bypass surgery. Further exclusions to HBO ing electrocardiograms and respiratory traces. Measuring of
were the inability to equilibrate pressure in the middle ear noninvasive blood pressure inside the hyperbaric chamber
space secondary to upper respiratory tract infections, otitis was done in an automatic reading system, which measures
or rhinitis, severe claustrophobia, and chronic obstructive the pressure displayed from the oscillometric method at pre-
pulmonary disease. set intervals. All monitoring devices, drug protocols, and
From 92 patients with acute myocardial infarction origi- other procedures in the intensive care unit continued when
nally considered for the study, 18 were subsequently ex- patients were discharged inside the chamber. Monoplace
cluded. Five patients were excluded because of rhythm and chambers exclude possible nurse assistance, so these cham-
hemodynamic instability in the emergency room. Six patients bers have an option of emergency decompression within at
refused coronary angiography, which also represents exclu- least 1 minute, depending on the nature of critical situation.
sion criteria in this study. Three patients refused entry into All patients were assessed clinically at study entry for the
the HBO chamber: two because they felt claustrophobia in presence or absence of heart failure on the basis of Killip
the chamber and one because of chronic otitis media. Four criteria. Creatine phosphokinase samples were obtained on
patients had chronic obstructive pulmonary disease with admission, every 4 hours for the first 24 hours, and afterward
marked CO2 retention. In patients who started HBO, there on daily basis.
were no complications inside the chamber or after the treat- Coronary angiography was performed after hospital dis-
ment and no need for urgent decompression. Thus, the final charge. Perfusion of the infarct-related artery was assessed by
study population consisted of 74 patients (63 men, 11 wom- using criteria from the Thrombolysis In Myocardial Infarction
en; mean age, 55 7 years). (TIMI) trial.11 Successful reperfusion was coded as TIMI
grade 3.
Study procedure
Streptokinase was administered at the dose of 1.5 mU/L Echocardiography
over 30 to 60 minutes, followed by intravenous heparin infu- Two-dimensional echocardiography was performed with an
sion. With a random number table, patients were randomly Acuson 128 imaging system on day 1 after thrombolysis or
assigned to streptokinase therapy alone (HBO group, 37 immediately after thrombolysis plus HBO treatment, on day
patients) or streptokinase with HBO (HBO group, 37 pa- 2, and after 3 weeks in all patients. All measurements were
tients). The patients randomly assigned to streptokinase plus performed off-line, calculated from the mean value of 3 best
HBO were transferred to the hyperbaric unit in the first 24 consecutive cardiac cycles. The physician, who assessed left
hours from the onset of symptoms and after thrombolytic ventricular function, was blinded to the random assignment
therapy. The time from cessation of thrombolytic therapy to status of the patient. Left ventricular volumes and EF were
HBO ranged from 45 minutes to 18 hours, with average time determined from apical 2- and 4-chamber views, using the
of 10 hours (Figure 1). The patients randomly assigned to Simpson biplane formula. The left ventricular volumes, end-
American Heart Journal
Dekleva et al 3
Volume 148, Number 4

Table I. Demographic, clinical, and angiographic Table II. Medical treatment of patients during in-hospital
characteristics of patients period


(n 37) (n 37) value (n 37) (n 37) value

Age (y) 55 7 54 8 NS Heparin 37 (100%) 37 (100%) NS

Sex (F/M) 8/29 3/34 NS Aspirin 36 (97%) 36 (97%) NS
Hypertension 14 (38%) 13 (35%) NS Oral anticoagulation 5 (14%) 8 (22%) NS
Diabetes mellitus 8 (22%) 2 (5%) 0.05 Nitroglycerin IV 7 (19%) 8 (22%) NS
Smoking 30 (81%) 27 (73%) NS Long-acting nitrates 30 (81%) 31 (84%) NS
Killip class 2 2 (5%) 5 (14%) NS Calcium channel blockers 1 (3%) 1 (3%) NS
Time to STK (h) 2.4 1.6 3.0 1.5 NS -Blockers 26 (70%) 23 (62%) NS
Anterior MI 14 (38%) 16 (43%) NS Digitalis 1 (3%) 1 (3%) NS
Peak CK value (U/L) 989 643 1529 1187 0.05 Diuretics 3 (8%) 5 (14%) NS
Multivessel CAD 19 (51%) 20 (54%) NS ACE inhibitors 8 (22%) 12 (32%) NS
TIMI 3 flow 22 (59%) 22 (59%) NS
Collaterals 9 (24%) 9 (24%) NS
Cardiac mortality 0 (0%) 1 (3%) NS
Figure 2
CAD, Coronary artery disease; CK, creatine phosphokinase; STK, streptokinase.

diastolic and end-systolic, were normalized for body surface

area and expressed as indexes (EDVI and ESVI).12

Statistical analysis
The unpaired t test and 2 test were used to test the differ-
ences between 2 groups of patients. The paired t test was
used to compare initial left ventricular volume indexes and
EF, with results performed after 3 weeks. Analysis of variance
was used for analyzing repeated measures of left ventricular
volumes indexes, and EF. Probability values of .05 were
considered statistically significant.

Changes of ESVI in acute myocardial infarction in HBO and

HBO groups of patients. Large box/upper border, 75% percen-
Demographic, clinical, and angiographic data tile; large box/lower border, 25% percentile; line in the middle of
Patient demographics and clinical and angiographic the large box, median; small box inside large one, mean value.
data are listed in Table I. There was no significant dif- *Confidence interval, 1% to 99%.
ference between study groups with regard to the age,
sex, prevalence of hypertension, and smoking history.
According to anamnesis and adjusted analysis for dia-
betic status at baseline, there were more diabetic pa-
tients in the HBO group, but these distributions have ACE inhibitors, anticoagulants, aspirin, -blockers, long-
no obvious influence on the final results. The distribu- acting nitrates, intravenous nitroglycerin, calcium channel
tion of localization of myocardial infarction was similar inhibitors, digitalis, and diuretics (P not significant).
in both study groups. Patients in both groups were
evenly distributed in either Killip class I or II. With Left ventricular function and remodeling
regard to coronary angiography, there were no signifi- In the current study, using serial echocardiography
cant differences between the two groups in infarction examinations, we were able to observe the pattern of
artery patency, single or multivessel coronary artery changes of left ventricular volumes and EF in respect
disease, or collateral vessel presence. However, pa- to HBO treatment and to compare the baseline values
tients receiving thrombolytic therapy alone showed a with subsequent studies up to 3 weeks.
higher peak creatine phosphokinase activity compared The changes in left ventricular volumes and EF are
with the HBO group (989 vs 1529 IU, P .05). presented in Figure 2, Figure 3, and Figure 4. Initial
As shown in Table II, both groups of patients re- left ventricular volume indexes and EF were similar in
ceived similar medication before HBO, during their two study groups (P not significant). In patients
hospital stay, and at the time of discharge, including treated with thrombolysis only, there were significant
American Heart Journal
4 Dekleva et al
October 2004

to 50.81%). Thus, 3 weeks after acute myocardial in-

Figure 3
farction, the HBO group compared with the HBO
group of patients had lower ESVI (28.18 vs 36.68 mL/
m2, P .001) (Figure 2) and EDVI (56.2 vs 63.8 mL/
m2, P .001) (Figure 3) and higher EF (44.05% vs
50.,81%, P .001) (Figure 4).
As shown in the figures, the main effect of HBO was
achieved during the very first days of acute myocardial
infarction, with significant difference in ESVI and EF
on day 2 in favor of the HBO group. In the subse-
quent 3-week follow-up period, further changes of left
ventricular function indexes were slight and statisti-
cally nonsignificant.

The major original findings of this study relate to the
changes of left ventricular volumes in the time course
Changes of EDVI in acute myocardial infarction in HBO and estimated by echocardiography. We have shown that
HBO groups of patients. Large box/upper border, 75% percen- HBO and streptokinase in acute myocardial infarction
tile; large box/lower border, 25% percentile; line in the middle of reduced left ventricular volumes with associated in-
the large box, median; small box inside large one, mean value. crease in EF during the first 3 weeks after acute myo-
*Confidence interval, 1% to 99%. cardial infarction. In contrast, there was progressive
left ventricular dilation, with no change in EF in pa-
tients treated with thrombolysis only.

Figure 4 Comparison with previous studies

Left ventricular dilation in the first 3 weeks of myo-
cardial infarction is determined mostly by the expan-
sion process, infarct-related artery patency, and infarct
localization.1113,15 Popovic et al16 have shown that
the degree of EDVI increase for the period of 3 weeks
after acute myocardial infarction was 6.0% in patients
treated with streptokinase only. In our study, a similar
increase of EDVI was found in the HBO group but a
lower degree was found in the HBO group (55.9 to
63.8 mL/m2, 14.1%, vs 55.7 to 56.2 mL/m2, 0.9%) (P
.001). Similarly, Chareonthaitawee et al14 have shown
that the degree of ESVI increase in thrombolytic-
treated patients was 12% in the acute phase, which
correlates well with our results in HBO patients
(30.1 to 36.7 mL/m2, 21.9%). In contrast, the decrease
Changes of EF in acute myocardial infarction in HBO and of ESVI during 3 weeks (30.4 vs 28.2 mL/m2, 7%) dem-
HBO groups of patients. Large box/upper border, 75% percen- onstrated a significant benefit of HBO. Concerning EF,
tile; large box/lower border, 25% percentile; line in the middle of the Intravenous Streptokinase in Acute Myocardial In-
the large box, median; small box inside large one, mean value. farction (ISAM) study demonstrated significant im-
*Confidence interval, 1% to 99%. provement of EF (5.3%) in patients treated with strep-
tokinase compared with the control group.17 This
difference was also seen in the study by White et al13
(10%), the GISSI-2 study18 (2% to 3%), the European
increases of ESVI (from 30.89 to 36,68 mL/m2) and Cooperative study Grupo Trial19 (4%), and the Western
EDVI (from 55.87 to 63.82 mL/m2) and decreases of Washington Trial20 (5%). In our study, the difference
EF (45.8% to 44.2%) during the first 3 weeks. Con- in EF was not observed in the HBO group, but in the
versely, in the HBO group, EDVI did not change sig- HBO group, EF significantly increased for 9.8%
nificantly (from 55.68 to 56.24 mL/m2), ESVI de- (46.3% to 50.8%). A favorable effect of the combina-
creased significantly (from 30.40 to 28.18 mL/m2), and tion of thrombolysis and HBO on left ventricular EF
EF improved during the follow-up period (from 46.27% has been demonstrated in the HOT MI study by Sta-
American Heart Journal
Dekleva et al 5
Volume 148, Number 4

vitsky et al.8 This multicenter study demonstrated tissue oxygen diffusion distance by a factor 3 or 4.
higher values of left ventricular EF at discharge time in Therefore, high oxygen tension and an increased
patients treated with adjunctive HBO compared with amount of available tissue oxygen, pressure difference
control subjects treated with thrombolysis only (48.4% between ischemic and nonischemic tissue, conse-
vs 51.7%).8 Both of these studies reported a benefit of quently improved penetration of oxygen into hypoxic
HBO as a single adjuvant therapy, without repeated tissues.6 Reduction in heart rate during compression
exposure, but Wada et al9,10 showed a protective ef- time that was based on decrease of sympathetic activ-
fect of repetitive HBO against ischemia in a brain ex- ity could be part of the mechanism of left ventricular
perimental model. According to these results, the best function improvement.5
tolerance against neuronal damage of the hippocam- Tissue oxygen tension remained elevated for some
pus of Mongolian gerbils was induced with pretreat- hours after cessation of HBO treatment.21 Thus, the
ment in 5 sessions of HBO, every other day, compared tissue remains oxygenated after completion of the
with single HBO pretreatment or with ischemic con- HBO treatment. According to our results, the most
trol group. powerful effect was on left ventricular remodeling and
Regarding prognostic importance of left ventricular left ventricular function at the first days of acute myo-
volumes, White et al13 have shown that left ventricular cardial infarction. The late effect could result in sus-
volumes were clearly associated with death; that is, tained beneficial effects even after decompression, al-
ESVI was the most powerful predictor of survival, and lowing improved myocardial salvage in that group of
the inclusion of EDVI or EF in a multivariate model patients who have late reperfusion.
added no further prognostic power. Other mechanisms may be responsible for improved
regional wall motion. Through favorable changes in
myocardial oxygen supply and demand, HBO im-
Myocardial enzymes
proved contraction of hibernating myocardium after
Standard reflow with thrombolysis is followed with
myocardial infarction that is indicated in the study
significant creatine phosphokinase enzyme leakage or
conducted by Swift et al.21 In our study, the increase
washout effect, evidenced as an increased total activity
of global left ventricular function is followed by im-
in blood after thrombolysis. In our study, peak creat-
provement of global systolic function in HBO pa-
ine phosphokinase level was 35.3% lower in the
tients compared with the HBO group.
HBO group of patients than in the HBO group.
During left ventricular remodeling, there are struc-
Very similar data were reported in a randomized pilot
tural changes in coronary microcirculation followed by
trial by Shandling et al,7 demonstrating that mean
decreased capillary density, with enlarged diffusion
creatine phosphokinase level at 12 and 24 hours
distances for oxygen and disturbed perfusion of the
was reduced in patients given HBO by approxi-
capillary bed.22 Microvascular obstruction after reper-
mately 35% (P .03). An attenuated rise in creatine
fusion may be the consequence of low or no reflow
phosphokinase (7.5%) in patients treated with
phenomena. These obstructive myocardial zones have
thrombolysis and HBO is one of the main remarks of
a great influence on the left ventricular remodeling
the HOT MI study by Stavitsky et al.8 Also, in an ani-
process and left ventricular function.23,24 Favorable
mal study conducted by Thomas et al,6 HBO com-
effects of HBO in decreasing leukocyte endothelial ad-
bined with thrombolysis restored 95% of normal oxi-
herence and improvement of angiogenesis is also a
dative enzyme activity and decreased the release of
contributory mechanism.23,25
creatine phosphokinase into blood, thus better pre-
There was initially concern that an increase in free
serving myocardial fiber integrity.
oxygen radicals, occurring by the high oxygen tension
state of HBO treatment, would emphasize tissue reper-
Mechanism of improvement in left ventricular function fusion injury.1,25 However, the results from our study
In the presence of a critical coronary artery stenosis, do not suggest that this mechanism occurs to any no-
the oxygen demand changes. In these circumstances, ticeable clinical sign in patients treated with 2 ATA
increased dissolved oxygen fraction under hyperbaric HBO protocol. Recent and present investigators have
conditions could be enough to meet resting cellular shown that HBO lessens or may inhibit reperfusion
requirements without any contribution from oxygen injury by protection of oxidative metabolism in reper-
bound to hemoglobin from increased blood flow.1 fusion-stunned myocardium.23,25,26 Results of the stud-
The quantity of oxygen carried in the plasma and ies conducted by Wada et al showed an HBO effect on
tissue fluid under hyperbaric conditions in this study is immunoreactivity to apoptosis-regulating protein
increased 10-fold compared with breathing room air. (Bc1-2, Bax) and manganese superoxide dismutase (Mn
The net effect, with an HBO treatment at 2 ATA abso- SOD), a radical scavenging system. This protective
lute pressure, is an approximately 25% enhanced oxy- mechanism of repeated HBO pretreatment induced
gen blood content and consumption and increased tolerance against ischemic neuronal damage in gerbil
American Heart Journal
6 Dekleva et al
October 2004

hippocampus. Protection against mitochondrial alter- 7. Shandling AH, Ellestad MH, Hart GB, et al. Hyperbaric Oxygen
ations after ischemia through Mn SOD and/or Bc1-2 and Thrombolysis in Myocardial Infarction: the HOT MI pilot
expression may be related to induction of ischemic study. Am Heart J 1997;134:544 50.
tolerance by HBO.10,27 8. Stavitsky Y, Shanding AH, Ellestad MH, et al. Hyperbaric Oxygen
and Thrombolysis in Myocardial Infarction: the HOT MI Ran-
domized Multicenter Study. Cardiology 1998;90:131 6.
Study limitations 9. Wada K, Ito M, Miyazama T, et al. Repeated hyperbaric oxygen
The data apply to the patients treated only with induces ischemic tolerance in gerbil hippocampus. Brain Res
streptokinase, and the results may be different for the 1996;18:1520.
patients treated with other lytic agents or combination 10. Wada K, Miyzama T, Nomura N, et al. Preferential conditions for
therapies. and possible mechanism of induction of ischemic tolerance by re-
Because HBO treatment requires additional logistic peated hyperbaric oxygenation in gerbil hippocampus. Neurosur-
support, we excluded from the study high-risk patients gery 2001;49:160 7.
with severe heart failure as well as patients with signif- 11. TIMI Study Group. The Thrombolysis In Myocardial Infarction
icant electrical complications, who may actually have (TIMI) trial: phase I findings. N Engl J Med 1985;312:932 6.
12. Shiller N, Shah PM, Crawford M, et al. Recommendations for
the greatest benefit from combined HBO and throm-
quantitation of the left ventricle by two-dimensional echocardiog-
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raphy. J Am Soc Echocardiogr 1989;2:358 68.
In the current study, the time from streptokinase to
13. White HD, Noris RM, Brown MA, et al. Left ventricular end-systolic
HBO treatment was prolonged because of the distance volume as the major determinant of survival after recovery from
between hyperbaric unit and the coronary care unit. myocardial infarction. Circulation 1987;76:44 51.
A larger group of patients treated with HBO after 14. Chareonthaitawee P, Christian TF, Hirose K, et al. Relation of ini-
thrombolysis may demonstrate event-free survival ben- tial infarct size to left ventricular remodeling in the year after acute
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Our data indicate the adjunctive effect of HBO after
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thrombolysis, resulting in attenuated creatine phos-
latation after myocardial infarction: serial echocardiographic fol-
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Volume 148, Number 4

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